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Mycobacterium tuberculosis 38-kDa antigen induces endoplasmic reticulum stress-mediated apoptosis via toll-like receptor 2/4

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Abstract

Endoplasmic reticulum (ER) stress responses play critical roles in the pathogenesis of tuberculosis. To investigate the regulatory role of the ER stress response in 38-kDa antigen-induced apoptosis, we examined the relationship between the ER stress response and apoptosis in bone marrow-derived macrophages (BMDMs) stimulated with Mycobacterium tuberculosis antigen (38-kDa Ag). The expression of ER molecular chaperones, including C/EBP homologous protein (CHOP), glucose-regulated protein (Bip) and phosphorylated alpha subunit of eukaryotic initiation factor 2, was induced in BMDMs stimulated with the 38-kDa Ag. Interestingly, 38-kDa Ag-stimulation induced apoptosis via activation of caspase-12, -9 and -3. However, 38-kDa Ag-induced apoptosis was significantly reduced in TLR2- and TLR4-deficient macrophages. Because toll-like receptors (TLRs) initiate the activation of mitogen-activated protein kinase (MAPK) signaling cascades, we evaluated the effect of MAPK activation on ER stress. The 38-kDa Ag activated Jun N-terminal kinase, extracellular signal-regulated kinase and p38 phosphorylation. MAPK signaling induced the secretion of proinflammatory cytokines such as MCP-1, TNF-α and IL-6. The 38-kDa Ag-induced MCP-1 was especially associated with the induction of MCP-1-induced protein (MCPIP), which increased the generation of reactive oxygen species (ROS) and ER stress. To investigate the role of MCPIP in ROS-induced ER stress by 38-kDa Ag stimulation, we transfected MCPIP siRNA into RAW264.7 cells before 38-kDa Ag stimulation, and measured the generation of ROS and expression of ER molecular chaperones. ROS production and CHOP expression were decreased by the silencing of MCPIP induction. Our results demonstrate that the expression of MCPIP by 38-kDa Ag stimulation is increased through a TLR–MAPK-dependent signaling pathway, and leads to ER stress-induced apoptosis. In conclusion, MCPIP is important for host defense mechanisms in mycobacterial pathogenesis.

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Abbreviations

ER:

Endoplasmic reticulum

TB:

Tuberculosis

ROS:

Reactive oxygen species

CHOP:

C/EBP homologous protein

MCPIP:

Monocyte chemotactic protein-1 inducible protein

Mtb:

Mycobacterium tuberculosis

eIF2α:

Eukaryotic translation initiation factor 2A

GADD153:

Growth arrest and DNA damage induced gene-153

UPR:

Unfolded protein response

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013R1A1A2009736), and by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A121496). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

The authors have declared that no competing interests exist.

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Authors and Affiliations

  1. Department of Microbiology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 301-747, South Korea

    Yun-Ji Lim, Ji-Ae Choi, Jeong-Hwan Lee, Chul Hee Choi, Hwa-Jung Kim & Chang-Hwa Song

  2. Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, 301-747, South Korea

    Yun-Ji Lim, Hwa-Jung Kim & Chang-Hwa Song

  3. Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, 301-747, South Korea

    Chul Hee Choi, Hwa-Jung Kim & Chang-Hwa Song

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  1. Yun-Ji Lim
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Correspondence to Hwa-Jung Kim or Chang-Hwa Song.

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10495_2014_1080_MOESM1_ESM.eps

Supplementary material 1 Fig. S1. ER stress response and caspases activation by 38-kDa Ag was TLR-dependent. Immunoblot analysis of ER stress sensor molecules and caspases in (a) TLR2- or (b) TLR4-defecient BMDMs stimulated with 38-kDa Ag for 48 h. The data are shown as the means ± SD of three independent experiments. *p <0.05, ** p <0.01 and *** p <0.001. (EPS 2472 kb)

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Lim, YJ., Choi, JA., Lee, JH. et al. Mycobacterium tuberculosis 38-kDa antigen induces endoplasmic reticulum stress-mediated apoptosis via toll-like receptor 2/4. Apoptosis 20, 358–370 (2015). https://doi.org/10.1007/s10495-014-1080-2

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